LEONOR MICHAELIS 



an electron transfer may occur once in a while. Now, the transfer 

 of a single electron establishes the free radical, and from here on the 

 second step of oxidation takes place readily and spontaneously. In 

 order to account for the fact that the interaction of succinic acid and 

 fumaric acid in the presence of the enzyme and methylene blue is 

 reversible, one must postulate also that the enzyme can combine re- 

 versibly not only with succinic acid, but also with fumaric acid; and 

 not only with methylene blue, but also with leucomethylene blue. 

 Such an assumption is not unreasonable and is supported by the ob- 

 servation that, in very many cases, molecular species of a structure 

 similar to that of the specific active substance, inhibit the function of 

 that substance and so compete with it for the enzyme. Out of the 

 numerous examples discovered in recent years, one may recall the 

 antagonism of j&-aminobenzoic acid and sulfanilamide. 



At this stage of the argument, we have reached the realm of 

 speculation. Any further advance depends on the clarification of the 

 structure of the enzymes and especially of the steric structure of the spe- 

 cific proteins. It will be the aim of future work to show that the 

 specific structure of the enzyme forces the substrates attached to the en- 

 zyme to stay in such a mutual orientation as to permit an electron 

 transfer, which will not occur with a reasonable probability on a free 

 collision. A similar principle may underlie all specific enzymic 

 reactions, as well as those not concerned with oxidation-reduction. 

 The astounding fact that all enzymes are or contain a protein of specific 

 structure suggests that the attachment of the substrate to the enzyme 

 with its specific protein structure increases the chance of a thermo- 

 dynamically possible reaction by forcing a spatial orientation of the 

 interacting molecules which has practically no opportunity to occur 

 on spontaneous haphazard collision, and moreover, by holding the 

 interacting molecules in this specific orientation for a length of time 

 very much longer than on the occasion of a haphazard collision by 

 thermal motion. This is the way in which we may imagine the 

 activation energy is overcome, and in which out of a vast number of 

 thermodynamically permissible reactions only a few reactions service- 

 able for the metabolism are selected. 



The road for the exploration of the mechanisms of individual 

 metabolic catalyses will be long. Although it is still far ahead, one is 

 encouraged to believe that the correct road sign has been found. 



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